This application is a 371 of PCT/JP98/02641 filed Jun. 16, 1998.
1. Field of the Invention
The present invention relates to nitrogen-containing heterocyclic compounds which inhibit the aggregation of platelets, and pharmaceutical compositions comprising the compound as an effective ingredient, which are effective for the treatment and prophylaxis of thrombotic diseases.
2. Background Art
Diseases in the cardiovascular system have increased with the change of diet or the increase of the aged population, and about 50% of these diseases is regarded to be caused by thrombus.
Platelet as an ingredient of plasma participates largely in the production of thrombus in body. For the treatment and prophylaxis of thrombotic diseases, there have thus been used clinically pharmaceuticals which suppress the function of platelets and inhibit the aggregation of platelets, for example aspirin which suppresses cyclooxygenase and cyclopyridine which activates adenylcyclase.
Recently, the analysis of glycoproteins has been progressively analyzed. It has been elucidated that a membrane glycoprotein referred to as GPIIb/IIIa has a function as a receptor of fibrinogen. Thus, an antagonist of the membrane glycoprotein GPIIb/IIIa has been expected to be effective for the treatment and prophylaxis of the thrombotic diseases as a platelet aggregation inhibitor having a new reaction mechanism (Trends in Pharmacological Science, 13, 413, 1992). There has been known as the compounds having such antagonistic effects monoclonal antibody (Ann. New York Acad. Sci., 614, 193, 1991), tripeptide derivatives comprising arginine-glycine-aspartic acid (J. Med. Chem., 35, 2040, 1992), amidinophenyl derivatives (J. Med. Chem., 35, 4393, 1992; Japanese Patent Laid-Open Publication No.4-264068, Japanese Patent Laid-Open Publication No. 4-334351, EP 483667, EP 525629, EP 529858, EP 537980, WO 9307867, WO 9402472, and the like), tyrosine derivatives (J. Med. Chem., 35, 4640, 1992), piperidine derivatives (EP 512831, EP 540334, EP 578535, and the like).
On the other hand, there have been desired as therapeutic and prophylactic agents of thrombotic diseases a highly selective agent having no side effects such as hemorrhage and a highly active antagonist effective even on its oral administration.
The present inventors have now prepared novel nitrogen-containing heterocyclic compounds having extremely high oral absorbing capacity.
The compounds according to the present invention are the compounds represented by the following general formula (I), and pharmaceutically acceptable salts and solvates thereof. 
wherein
A represents CH2 or CO,
B represents a group xe2x80x94(CH2)kxe2x80x94, where k is an integer of 1-4, or xe2x80x94(CH2)mxe2x80x94COxe2x80x94, where m is an integer of 0-3,
X and Y, which are different from each other, represent N or CH,
W represents an ester moiety which can be removed under the physiological condition,
Z represents the group (II) or (III) 
xe2x80x83wherein
n is an integer of 1-3,
D represents the group xe2x80x94Vxe2x80x94(CH2)pxe2x80x94COOR, where V represents xe2x80x94Oxe2x80x94 or a bond, p is an integer of 1-4, R represents a hydrogen atom, C1-8 alkyl, which may be substituted by a halogen atom, C3-8 cycloalkyl, benzyl, five- to eight-membered saturated cycloalkyl containing an oxygen or sulfur atom, 1,3-bis(C1-6alkoxy)propan-2-yl, 1,3-bis(C1-6alkylthio)propan-2-yl, C1-6alkyl-(OCH2CH2)qxe2x80x94 where q is an integer of 1-3, C1-6alkyl-(SCH2CH2)rxe2x80x94 where r is an integer of 1-3, Rxe2x80x2Rxe2x80x3NCOxe2x80x94(CH2)sxe2x80x94 where s is an integer of 1-3, and Rxe2x80x2 and Rxe2x80x3 independently represent a hydrogen atom or C1-6alkyl, or an ester moiety which may be removed under a physiological condition,
R1 represents a hydrogen atom or C1-6 alkyl which may be substituted by carboxyl, lower alkoxyl, carbamoyl, or phenyl.
In the present specification, alkyl, alkenyl and alkynyl groups may be either of straight chain or branched chain. The term xe2x80x9chalogen atomxe2x80x9d means herein fluorine, chlorine, bromine or iodine atoms. The term xe2x80x9carylxe2x80x9d means preferably phenyl, naphthyl or tolyl. Furthermore, the term xe2x80x9caralkylxe2x80x9d means preferably benzyl, phenylethyl (phenethyl), or methylbenzyl.
In the formula (I), A represents CH2 or CO. According to the preferred embodiment of the present invention, the compound of the formula (I) wherein A represents CO is preferred.
In the formula (I), B represents the group xe2x80x94(CH2)kxe2x80x94, wherein k is an integer of 1-4, preferably 1 or 2, or the group xe2x80x94(CH2)mxe2x80x94COxe2x80x94, wherein m is an integer of 0-3, preferably 0, 1 or 2. According to the preferred embodiment of the present invention, B preferably represents the group xe2x80x94(CH2)mxe2x80x94COxe2x80x94, more preferably the group xe2x80x94CH2xe2x80x94COxe2x80x94.
In the formula (I), X and Y are different from each other and represent N or CH. According to the preferred embodiment of the present invention, X represents CH and Y represents N.
In the formula (I), W represents an ester moiety which can be removed under a physiological condition. The first example of the preferred ester moiety is the following group represented by the formula (a): 
wherein R2 and R3 represent independently a hydrogen atom or C1-6 alkyl (preferably C1-4 alkyl), R4 represents C1-10 alkyl (preferably C1-6 alkyl, more preferably C1-4 alkyl), C2-10 alkenyl (preferably C2-6 alkenyl, more preferably C2-4 alkenyl), C2-5 alkynyl, aryl such as phenyl, naphthyl or tolyl, or C3-8 cycloalkyl (preferably C5-8 cycloalkyl). According to the preferred embodiment of the present invention, the compounds of the formula (I) having the group (a) where R2 represents a hydrogen atom, R3 represents a hydrogen atom or C1-6 alkyl, and R4 represents C1-6 alkyl are preferred.
The second example of the preferred ester moiety is the following group represented by the formula (b): 
wherein R5 represents a hydrogen atom, C1-6 alkyl (preferably C1-4 alkyl), or C6-8 aralkyl such as benzyl, phenylethyl (phenethyl) or methylbenzyl, R6 and R7 independently represent a hydrogen atom or C1-6 alkyl (preferably C1-4 alkyl). According to the preferred embodiment of the present invention, the compounds of the formula (I) having the group (b) where R5 represents C1-6 alkyl, and R6 and R7 represent a hydrogen atom are preferred.
The third example of the preferred ester moiety is the following group represented by the formula (c): 
wherein R8, R9, R10 and R11 independently represent a hydrogen atom, C1-6 alkyl or C6-8 aralkyl, R12 and R13 independently represent a hydrogen atom or C1-6 alkyl. According to the preferred embodiment of the present invention,in the group (c), R8, R9, R10 and R11 represent a hydrogen atom, R12 and R13 represent a hydrogen atom.
In the formula (I), Z represents the groups represented by the formula (II) or (III). In the groups (II) and (III), n is an integer of 1-3, preferably 1 or 2. This means that the number of the substituent D is 1-3, preferably 1 or 2. In addition, the substituent D is at the para or meta position to that of the substituent B.
In the group xe2x80x94Vxe2x80x94(CH2)pxe2x80x94COOR in the group Z, V represents an oxygen atom or a bond. According to the preferred embodiment of the present invention, V is an oxygen atom. In the group, p is an integer of 1-4, preferably 1 or 2. In addition, R represents a hydrogen atom, C1-8 alkyl which may be substituted by a halogen atom, C3-8 cycloalkyl, benzyl, a five- to eight-membered saturated cycloalkyl group containing an oxygen or sulfur atom, preferably a five- to eight-membered saturated cycloalkyl group containing an oxygen atom, more preferably tetrahydropyranyl, 1,3-bis(C1-6 alkoxy)propan-2-yl, (preferably 1,3-bis(C1-4 alkoxy)propan-2-yl), 1,3-bis(C1-6 alkylthio)propan-2-yl (preferably 1,3-bis-(C1-4 alkylthio)propan-2-yl), C1-6 alkyl-(OCH2CH2)qxe2x80x94, wherein q is an integer of 1-3, C1-6 alkyl-(SCH2CH2)rxe2x80x94 wherein r is an integer of 1-3, Rxe2x80x2Rxe2x80x3NCOxe2x80x94(CH2)sxe2x80x94, wherein s is an integer of 1-3, and Rxe2x80x2 and Rxe2x80x3 independently represent a hydrogen atom or C1-6 alkyl (preferably C1-4 alkyl), or an ester moiety which can be removed under a physiological condition such as pivaloyloxymethyl, 1-(cyclohexyloxy-carbonyloxy)ethyl or (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl.
According to the preferred embodiment of the present invention, Z represents the group (II) where R represents C1-8 alkyl which may be substituted by halogen atoms, C5-8 cycloalkyl, benzyl, a five- to eight-membered saturated cycloalkyl group containing an oxygen or sulfur atom, 1,3-bis(C1-6 alkoxy)propan-2-yl, or a Rxe2x80x2Rxe2x80x3NCOxe2x80x94(CH2)sxe2x80x94, wherein s is 1, and Rxe2x80x2 and Rxe2x80x3 independently represent a hydrogen atom or C1-6 alkyl, respectively.
In the formula (I), R1 represents a hydrogen atom or C1-6 alkyl (preferably C1-4 alkyl), which may be substituted by carboxyl, C1-6 alkoxy, carbamoyl or phenyl.
A preferred class of the compounds of the present invention include the compounds wherein
Z represents the group (II) where R represents C1-8 alkyl which may be substituted by halogen atoms, C5-8 cycloalkyl, benzyl, a five- to eight-membered saturated cycloalkyl group containing an oxygen or sulfur atom, 1,3-bis(C1-6 alkoxy)propan-2-yl, or Rxe2x80x2Rxe2x80x3NCOxe2x80x94(CH2)sxe2x80x94, wherein s is 1, and Rxe2x80x2 and Rxe2x80x3 independently represent a hydrogen atom or C1-6 alkyl, respectively, and among these compounds are more preferably those wherein
W represents the group (a) where R2 represents a hydrogen atom, R3 represents a hydrogen atom or C1-6 alkyl, and R4 represents C1-6 alkyl,
W represents the group (b) where R5 represents C1-6 alkyl, and R6 and R7 represent a hydrogen atom,
W represents the group (c) where R8, R9, R10 and R11 represent a hydrogen atom, and R12 and R13 represent a hydrogen atom.
According to another preferred embodiment of the present invention, another preferred class of the compounds group of the present invention includes the compounds represented by the formula (I) wherein A represents CO, R1 represents a hydrogen atom, X represents CH, and Y represents N, and the more preferred compound group includes the compounds wherein A represents CO, R1 represents a hydrogen atom, X represents CH, Y represents N, and B represents xe2x80x94(CH2)mxe2x80x94COxe2x80x94.
The preferred examples of the compounds according to the present invention include
ethyl 4-[[2-oxo-4-(1-pivaloyloxymethoxycarbonylpiperidin-4-yl)piperazin-1-yl]acetyl]phenoxyacetate,
isopropyl 4-[[2-oxo-4-(1-pivaloyloxymethoxycarbonylpiperidin-4-yl)piperazin-1-yl]acetyl]phenoxyacetate,
ethyl 4-[[2-oxo-4-[1-(1-pivaloyloxyethyl)oxycarbonylpiperidin-4-yl]piperazin-1-yl]acetyl]phenoxyacetate,
ethyl 4-[[2-oxo-4-[1-(1-pivaloyloxy-2-methylpropyl)oxycarbonylpiperidin-4-yl ]piperazin-1-yl]acetyl]phenoxyacetate,
ethyl 4-[[4-(1-acetoxymethoxycarbonylpiperidin-4-yl)-2-oxopiperazin-1-yl]acetyl]phenoxyacetate,
isopropyl 4-[[4-(1-acetoxymethoxycarbonylpiperidin-4-yl)-2-oxopiperazin-1-yl]acetyl]phenoxyacetate,
cyclohexyl 4-[[4-(1-acetoxymethoxycarbonylpiperidin-4-yl)-2-oxopiperazin-1-yl]acetyl]phenoxyacetate,
ethyl 4-[[4-[1-(1-acetoxyethyl)oxycarbonylpiperidin-4-yl]-2-oxopiperazin-1-yl]acetyl]phenoxyacetate,
cyclohexyl 4-[[4-[1-(1-acetoxyethyl)oxycarbonylpiperidin-4-yl]-2-oxopiperazin-1-yl]acetyl]phenoxyacetate,
methyl 4-[[4-[1-(1-acetoxyetyl)oxycarbonylpiperidin-4-yl]-2-oxopiperazin-1-yl]acetyl]phenoxyacetate,
ethyl 4-[[4-[1-(1-acetoxypropyl)oxycarbonylpiperidin-4-yl]-2-oxopiperazin-1-yl]acetyl]phenoxyacetate,
cyclohexyl 4-[[4-[1-(1-acetoxy-2-methylpropyl)oxycarbonylpiperidin-4-yl]-2-oxopiperazin-1-yl]acetyl]phenoxyacetate,
ethyl 4-[[4-[1-acetoxy-2-methylpropyl]oxycarbonylpiperidin-4-yl]-2-oxopiperazin-1-yl]acetyl]phenoxyacetate,
isopropyl 4-[[4-[1-(1-acetoxy-2-methylpropyl)oxycarbonylpiperidin-4-yl]-2-oxopiperazin-1-yl]acetyl]phenoxyacetate,
ethyl 4-[[4-[1-(1-acetoxy-2,2-dimethylpropyl)oxycarbonylpiperidin-4-yl]-2-oxopiperazin-1-yl]acetyl]phenoxyacetate,
ethyl 4-[[2-oxo-4-[1-(1-propionyloxyethyl)oxycarbonylpiperidin-4-yl]piperazin-1-yl]acetyl]phenoxyacetate,
ethyl 4-[[2-oxo-4-[1-(propionyloxy-2-methylpropyl)oxycarbonylpiperidin-4-yl]piperazin-1-yl]acetyl]phenoxyacetate,
n-butyl 4-[[4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl oxycarbonylpiperidin-4-yl]-2-oxopiperazin-1-yl]acetyl]phenoxyacetate, and
ethyl 4-[[2-oxo-4-[(Z)-2-(3-phthalidyliden)ethyloxycarbonylpiperidin-4-yl)piperazin-1-yl]acetyl]phenoxyacetate.
The more preferred compounds include
ethyl 4-[2-oxo-4-(1-pivaloyloxymethoxycarbonylpiperidin-4-yl)piperazin-1-yl]acetyl]phenoxyacetate,
isopropyl 4-[[2-oxo-4-(1-pivaloyloxymethoxycarbonylpiperidin-4-yl)piperazin-1-yl]acetyl]phenoxyacetate, and
ethyl 4-[[4-(1-acetoxymethoxycarbonylpiperidin-4-yl)-2-oxopiperazin-1-yl]acetyl]phenoxyacetate.
The compounds according to the present invention can be formed into salts thereof. Such salts include pharmaceutically acceptable non-toxic salts. The preferred examples include inorganic salts such as sodium, potassium, magnesium or calcium salts; acid addition salts such as trifluoroacetate, hydrochloride, sulfate, acetate, oxalate, citrate, maleate, fumarate or methanesulfonate; amino acid salts such as glutamate or aspartate.
The compounds according to the present invention can be formed into thereof, preferably hydrates or ethanolate.
Furthermore, the compounds represented by the formula (I) may have asymmetric carbons, and the present invention includes all the isomers attributed to the presence of the asymmetric carbons.
The compounds according to the present invention can be preferably synthesized by the following methods (A)-(D).
Method (A): Synthesis of the compound wherein W represents the group (a) 
in which R2 and R3 have the same meanings as defined in the formula (I), J1 represents a halogen atom or a group which can be easily substituted nucleophilically, J2 represents a halogen atom or substituted phenoxy, X, Y, A, B, Z and R1 have the same meanings as defined in the formula (I), R4 represents c1-10 alkyl, C2-10 alkenyl, C2-5 alkynyl, aryl, or C3-8 cycloalkyl, M+ represents a metal ion, for example an ion of alkali or alkaline earth metal such as sodium, potassium, magnesium or calcium, or mercury, silver or zinc.
The method (A) can be carried out according to a manner described in J. Med. Chem., 34, 78 (1991) or Japanese Patent No. 2505728. In particular, the compound (IV) is reacted with the compound (V) in the presence of a base such as trimethylamine, 1,8-bis(dimethylamino)naphtalene, pyridine, potassium carbonate or sodium hydroxide in a halogenated solvent such as dichloromethane or an organic solvent such as diethyl ether, dioxane or tetrahydrofuran at a temperature of xe2x88x9230-35xc2x0 C., more preferably from 0xc2x0 C. to room temperature to give the compound (VI).
The compound (VI) thus obtained can be reacted with the compound (VII) R4COOxe2x88x92M+ in an alcohol, dimethylformamide or a solvent which is inert to a reactant as an organic acid (e.g., acetic acid or pivalic acid) at a temperature of 0-50xc2x0 C. to give the compound of the formula (I).
The compound (V) can be synthesized by the method described in WO 96/02503.
Method (B): Synthesis of the compound wherein W represents the group (a) 
E represents nitro, halogen, cyano, C1-6 alkyl or haloalkyl, and R2, R3, R4, X, Y, A, B, Z and R1 have the same meanings as defined in the formula (I).
The method (B) can be carried out according to a manner described in J. Med. Chem., 31, 318 (1988) or Japanese Patent No. 2510839. In particular, compounds of the formula (I) may be prepared by reacting the compound (VIII) with the compound (V) in the presence of a base such as triethylamine, diethylisopropylamine or proton sponge, or an inorganic base such as potassium carbonate in an aprotic polar solvent such as dimethylformamide, dimethylacetamide or dimethyl sulfoxide at a temperature of 0-40xc2x0 C., preferably 20-30xc2x0 C.
The compound (VIII) can be synthesized according to the following scheme: 
The compound (IX) (wherein E has the same meanings as defined in the formula (VIII)) is reacted with the compound (IV) (wherein R2, R3, J1 and J2 have the same meanings as defined above) in accordance with a manner discribed in J. Med. Chem., 31, 318 (1988) or Japanese Patent No. 2510839. The compound (X) thus obtained can be reacted with the compound (VII): R4COOxe2x88x92M+ in accordance with a manner described in the above cited literatures to give the compound (VIII).
The compound (XI) wherein E and J2 have the same meanings as above can be reacted with the compound (XII) wherein R2 has the same meanings as above in accordance with a manner discribed in Synthesis, pp. 407 (1988) to give the compound (X), which is further reacted with the compound (VII) as described above to give the compound (VIII).
Method (C): Synthesis of the compound wherein W represents the group (b) or (c) 
wherein T represents the group (b) or (c), E has the same meanings as defined in the compound (VIII), and X, Y, A, B, Z and R1 have the same meanings as defined in the formula (I).
The method (C) can be carried out in accordance with a manner described in J. Med. Chem., 39, 480 (1996). In particular, compounds of the formula (I) may be prepared by reacting the compound (XIII) with the compound (V) in the presence of a base such as triethylamine, diethylisopropylamine or proton sponge, or an inorganic base such as potassium carbonate in an aprotic polar solvent such as dimethylformamide, dimethylacetamide or dimethyl sulfoxide at a temperature of 0-40xc2x0 C., preferably 20-30xc2x0 C.
The compound (XIII) can be synthesized according to the following scheme: 
First, the compound (XIV) (wherein T represents the group (b) or (c), and J3 represents a substituent as a leaving group such as a halogen atom, a mesyl group or a tosyl group) is reacted in accordance with a manner described in Synth. Commun., 25, 3875 (1995). The compound (XV) (wherein T has the same meanings as defined above) thus obtained can be reacted with the compound (XI) in accordance with a manner described in J. Med. Chem., 39 480 (1996) to give the compound (XIV).
The compound wherein T represents the group (b) can be synthesized in accordance with the method described in Chem. Pharm. Bull., 32, 2241 (1984).
In addition, the compound wherein T represents the group (c) can be synthesized by the method described in Chem. Pharm. Bull., 31, 2698 (1988).
Method (D): Synthesis of the compound wherein X represents CH, Y represents N, and W represents the group (a) 
wherein W has the same meanings as defined in the formula (I), and A, B, Z and R1 have the same meanings as defined in the formula (I).
The compound of the formula (I) can be prepared by the reductive aminoalkylation reaction of the compound (XVI) and the compound (XVII) in an inert solvent such as 1,2-dichloroethane, tetrahydrofuran, acetic acid, and ethyl acetate under the catalytic hydrogenation condition in the presence of a hydrogenating metal agent such as sodium cyanoborohydride, lithium cyanoborohydride, sodium borohydride, lithium borohydride or sodium triacetoxyborohydride, or a catalyst such as palladium-carbon, palladium black, palladium hydroxide, platinum oxide or Raney nickel at a temperature of xe2x88x9220-100xc2x0 C., preferably at 0-70xc2x0 C. for 0.5-48 hours, preferably 1-24 hours.
The compound (XVI) can be synthesized according to the following scheme: 
The compound (IV) wherein R2, R3, J1 and J2 have the same meanings as defined above is reacted with the compound (XVIII) in an appropriate solvent, for example a halogenated solvent such as dichloromethane, an organic solvent such as diethyl ether, dioxane or tetrahydrofuran, water, or a mixture thereof in the presence of a base such as triethylamine, proton sponge, pyridine, potassium carbonate, sodium carbonate or sodium hydroxide at a temperature of xe2x88x9230-35xc2x0 C., preferably at xe2x88x9210-0xc2x0 C. for 0.5-4 hours, more preferably 0.5-1.5 hours to give the compound (XIX).
The compound (XIX) thus obtained wherein R2, R3 and J1 l have the same meanings as defined above and the compound (VII): R4COOxe2x88x92M+ prepared above are reacted in an alcohol, N,N-dimethylformamide or a solvent which is inert to a reactant as an organic acid, for example acetic acid or pivalic acid at a temperature of 0-50xc2x0 C. to give the compound of the formula (XVI).
The compound (XVII) can be synthesized according to the following scheme: 
The compound (XX) (wherein R5 represents H or an amino protecting group preferably a t-butoxycarbonyl group or a formyl group, and R1 and A have the same meanings as defined above) and the compound (XXI) (wherein Q represents a halogen atom, lower alkylsulfonyloxy, trifluoromethanesulfonyloxy, or arylsulfonyloxy, and B and Z have the same meanings as defined above) can be reacted in an inert solvent such as dimethylformamide, tetrahydrofuran and a mixed solvent thereof in the presence of a base such as metallic sodium, sodium hydride, calcium hydride, lithium n-butyl, lithium diisopropylamide, or lithium hexamethyldisilazide at a temperature of xe2x88x9280-30xc2x0 C., preferably 20-30xc2x0 C. for 10-60 minutes to give the compound (XXII) wherein R1, R5, A, B and Z have the same meanings as defined above. Alternatively, the compound (XX) and the compound (XXI) may be reacted in the presence of a tetraalkylammonium halide as a phase transfer catalyst together with an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate at a temperature of 20-150xc2x0 C., preferably 30-50xc2x0 C. for 8-72 hours, preferably 12-36 hours.
The compound (XVII) can be obtained by removing the protecting group R5 of the amino group of the compound (XXII) thus obtained, if necessary.
The compound (XX) can also be prepared by the method described in J. Am. Chem. Soc., 62, 1202 (1940).
It is thought apparent to the skilled person in the art that in the preparation procedure described above, the sequence of the synthesis is determined so that no side reactions occur at the functional group which will not participate in the reaction, and the functional groups may be protected with appropriate protecting groups in order to avoid undesirable reactions.
The compounds according to the present invention is hydrolyzed in the body to give the compound represented by the general formula (XXIII): 
wherein A, B, X, Y, Z and Rxe2x80x2 have the same meanings as defined in the formula (I), provided that R represents a hydrogen atom in the group xe2x80x94Vxe2x80x94(CH2)pxe2x80x94COOR as D in Z.
The compound inhibits the aggregation of platelets via the inhibition of the bonding of the platelet membrane protein GPIIb/IIIa to fibrinogen. That is to say, the compound of the formula (I) according to the present invention is the so-called prodrug of the compound of the formula (XXIII). In this connection, the compound of the formula (XXIII) may be optionally referred to as the active substance compound of the compound of the formula (I) according to the present invention. The compound of the formula (I) according to the present invention has a higher absorption capacity compared to that of the active substance compound even in its oral administration, and thus has an advantage that it has a high bioavailability in its oral administration. In addition, the compound of the formula (I) is believed to have few side effects such as hemorrhage or low selectivity of function.
The present inventors have also tried to prepare prodrugs from the compounds having the similar activities to those of the active substance compound of the compound (I) according to the present invention and described in WO 94/21599, particularly [[4-[[[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]amino]acetyl ]-o-phenylene]dioxy]diacetic acid by introducing an acetyloxyethoxycarbonyl group in the secondary amine position in the same manner as that in the compound of the formula (I) according to the present invention in accordance with the methods described in J. Alexander et al., J. Med. Chem., 34, 78 (1991), Japanese Patent No. 2505728 or Japanese Patent No. 2510839. That is, diethyl [[4-[[[[5-(1-acetoxyethyl)oxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridyl-2-yl]carbonyl]amino]acetyl]-o-phenyl ene]dioxy]-diacetate has been prepared. The compound, however, exhibited no high absorption capacity via its oral administration unlike the case of the compound of the formula (I) according to the present invention. This result is thought to indicate that the compound of the formula (I) according to the present invention has a high oral absorption capacity unexpected by the person skilled in the art.
Thus, the compound of the formula (I) according to the present invention is effective as a therapeutic agent and a prophylactic agent of thrombotic diseases caused by the aggregation of platelets, particularly cerebral infarction, cardiac infarction, angina pectoris, peripheral arterial occlusion, and the like, above all, as a therapeutic agent or a prophylactic agent of these diseases which can be administered orally.
Thus, according to the first embodiment of the present invention there is provided a pharmaceutical composition comprising an effective amount of the compound of the formula (I) according to the present invention or a pharmacologically acceptable salt or solvate thereof together with a pharmacologically acceptable carrier. The pharmaceutical composition is used as a platelet aggregation inhibitor or for the treatment or prophylaxis of thrombotic diseases. More specifically, it is used for the treatment or prophylaxis of cerebral infarction, cardiac infarction, angina pectoris or peripheral arterial occlusion.
Furthermore, according to another embodiment of the present invention, there is provided a therapeutic or prophylactic method of thrombotic diseases comprising administering an effective amount of the compound of the formula (I) according to the present invention or a pharmacologically acceptable salt or solvate thereof to animals including human.
According to a further embodiment of the present invention, there are provided the use of the compound of the formula (I) according to the present invention or a pharmacologically acceptable salt or solvate thereof for the therapy or prophylaxis of thrombotic diseases, and the use of the compound of the formula (I) according to the present invention or a pharmacologically acceptable salt or solvate thereof for preparing the therapeutic or prophylactic agents of thrombotic diseases.
The compound according to the present invention, which may be administered directly as the compound, is preferably administered in the form of a pharmaceutical composition comprising the compound according to the present invention as an effective component. The pharmaceutical composition can be prepared in appropriate dosage forms depending on the dosage routes, specifically in either one of the dosage forms such as oral agents, e.g. especially tablets, capsules, granules, powder, pills, fine particles or troches, rectal agents, oily suppositories, aqueous suppositories, or the like.
A variety of these preparations can be prepared by the conventional method with excipients, fillers, bonding agents, humidifying agents, disproportionating agents, surface active agents, lubricating agents, dispersing agents, buffers, preservatives, dissolving aids, antiseptic agents, flavoring agents, analgesic agents, stabilizing agents, and the like. The non-toxic acceptable additives described above include for example lactose, fructose, glucose, starch, gelatin, magnesium carbonate, synthetic magnesium silicate, talc, magnesium stearate, methyl cellulose or a salt thereof, gum arabic, polyethylene glycol, syrup, petrolatum, glycerol, ethanol, propylene glycol, citric acid, sodium chloride, sodium sulfite, sodium phosphate, and the like.
The content of the compounds of the present invention in the pharmaceutical composition depends on their dosage forms, and is generally in the range of 1-70% by weight, preferably about 5-50% by weight of the total composition.
The dose is determined appropriately in consideration of the use, the age and sex of the patient and the severity of the condition, and for the treatment of thrombotic diseases the compound is administered generally in an amount of about 0.1-1,000 mg, preferably 1-200 mg per day for an adult, which can be administered once or in several sub-divided portions.